Obesity is the most common metabolic disease, resulting from the ingestion of calories in excess of ongoing requirements. Increased prevalence of obesity has resulted in rapidly accelerating rates of obesity related disorders such as type 2 diabetes and cardiovascular disease. The pathogenesis of obesity remains incompletely understood. In the current application, we propose to investigate a novel role for synphilin-1 in food intake and body weight control. Synphilin-1, a cytoplasmic protein, interacts with alpha-synuclein and parkin and has implications in Parkinson's disease pathogenesis related to protein aggregation. Through work examining the phenotype of a synphillin-1 transgenic mouse (SP1), we have evidence that synphilin-1 over- expression significantly increases body weight and does so through increasing food intake. We have found that synphilin-1 is highly expressed in neurons of hypothalamic nuclei involved in energy balance, suggesting that synphilin-1 may be affecting energy balance by modulating hypothalamic signaling. Our preliminary data suggest that synphilin-1 may affect food intake and body weight through increases in orexigenic genes: NPY and AgRP expression in hypothalamic neurons. Recently, studies have suggested that AMP-activated kinase (AMPK) is a central neuronal energy sensor that plays a major role in maintaining energy homeostasis. Our preliminary data showed that expression of human synphilin-1 increased AMPK phosphorylation in cultured N1E-115 cells and at the PVN site, and further showed that synphilin-1 interacted with AMPK as indicated by co-immunoprecipitation. Thus, in this proposal, we will test the hypothesis that synphilin-1 modulates hypothalamic feeding related gene expression and AMPK signaling cascades resulting in hyperphagia and obesity. In Aim 1, we will characterize changes in food intake, body weight and patterns of hypothalamic gene expression in responses to overexpression of synphilin-1. We will specifically assess the bases for the increased meal size that characterizes the hyperphagia in SP1 mice by testing responses to central and peripheral peptide administration and characterizing their taste preferences. In Aim 2, we will investigate the role of endogenous hypothalamic synphilin-1 in response to alterations in metabolic status. In Aim 3, we will test the hypothesis that synphilin-1 alters AMPK signaling cascades and its related cell energy events in an in vitro cell culture system. In Aim 4, we will test the hypothesis that synphilin-1 activates AMPK signaling in hypothalamus resulting in hyperphagia and obesity in vivo using overexpression and siRNA knockdown approaches. These studies will provide insight into the molecular mechanisms underlying synphilin-1-induced hyperphagia and obesity, will enlarge our knowledge of the biological functions of synphilin-1, and may provide a unique genetic obesity model for future studies of the pathogenesis of obesity.